Following tissue injury, cells are mobilized from the bone marrow to the site of injury. As the inflammatory response subsides, the wound is remodeled to form stratified epithelia over a collagen-rich matrix containing mesenchymal cell types. Although the bone marrow contribution to the inflammatory response is well established, the long-term fate and role of bone marrow-derived cells in a healed cutaneous wound remains less clear. The bone marrow harbors stem cells capable of differentiating along hematopoietic cell and mesenchymal cell lineages. Both stem cell types have a high-degree of plasticity and are capable of contributing cells to multiple tissues, including skin. To better understand the role that bone marrow cells play in wound repair, we developed a chimeric mouse wound model in which mesenchymal stem cells (MSC) from EGFP transgenic mice are transplanted into marrow-ablated C57BL mice. In this grant, we explore the hypothesis that bone marrow-derived mesenchymal stem cells are a critical source of CD45- cells that regulate TGFbeta and collagen production in the skin and wound. We will test our hypothesis with the following specific aims: 1. To determine the cellular phenotype and differentiation capability of bone marrow-derived MSC in normal and wounded murine skin. 2. To determine the effect of MSCs on the production of TGF-Beta isoforms, collagen type I, and collagen type by keratinocytes and fibroblasts. 3. To determine whether bone marrow-derived MSC can reverse diabetes impaired wound healing. 4. To determine whether bone marrow-derived MSC are critical for wound healing.